Transdermal compositions of ibuprofen and methods of use thereof

ABSTRACT

A transdermal composition comprising ibuprofen or salts thereof and a gelling agent which can be used for the treatment of such disorders as pain, inflammation, arthritis, muscle spasm and associated symptoms in humans and animals.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of application Ser. No. 13/463,626,filed on May 3, 2012, which claims the benefit of priority ApplicationSer. No. 61/482,058, filed on May 3, 2011. Each of the aforementionedrelated applications is expressly incorporated herein by reference inits entirety.

FIELD OF THE INVENTION

The present invention relates to ibuprofen or salts thereof,particularly the S-enantiomer of ibuprofen, in compositions fortransdermal administration. The present invention particularly relatesto ibuprofen gel formulations.

INTRODUCTION

Ibuprofen (2-(4-isobutylphenyl)propionic acid) is a common nonsteroidalanti-inflammatory drug (NSAID) for the treatment of pain, inflammation,arthritis, muscle spasm and associated symptoms in humans and animals.Ibuprofen is a racemic mixture of “S” and “R” enantiomers.

Ibuprofen is most commonly administered orally. Topical administrationof ibuprofen would offer local and enhanced drug delivery to affectedtissues. However, topically administered ibuprofen would penetrate theskin slowly and in small quantities. Overcoming poor penetration ofibuprofen through the skin of humans and animals is a major challenge totransdermal delivery of ibuprofen. There exists a need to providecompositions which are more effective for transdermal delivery ofibuprofen.

BRIEF DESCRIPTION OF THE FIGURE

FIG. 1 is a graph illustrating the results from an in vitro 24-hourcomparative permeation study of ibuprofen through human skin comparingpermeation of different ibuprofen gel formulations of the invention, anda comparative formulation.

FIG. 2 is a diagram illustrating the design space showing therelationship between the concentrations of water and hydroxypropylcellulose (hpc), and the physical state of the formulations (viscousliquid, very viscous liquid or semi-solid).

FIG. 3 is a diagram illustrating the unweighted pharmaceutical elegancescores.

FIG. 4 is a diagram illustrating the weighted pharmaceutical elegancescores.

FIG. 5 is a diagram illustrating the Percent Viability of EpiSkin® MTTTest samples (Mean SD, n=6).

SUMMARY OF THE INVENTION

In various embodiments, the invention provides transdermal compositionsincluding ibuprofen (2-(4-isobutylphenyl)propionic acid) or saltsthereof, a gelling agent and a non-volatile solvent. In otherembodiments, the invention provides transdermal gel compositionsincluding ibuprofen, a gelling agent, a lower alkyl glycol, and a loweralkyl alcohol. In further embodiments, the transdermal compositionsinclude one or more skin penetration enhancer(s).

DETAILED DESCRIPTION OF THE INVENTION

As used herein, the terms “formulation” and “composition” areinterchangeable.

As used herein, the terms “topical administration,” or “transdermaladministration,” means direct contact, layering or spreading upon dermaltissue, especially outer skin (epidermis) or membrane.

As used herein, all percentages are by weight of the total compositionunless otherwise specified.

In certain embodiments, the compositions of the invention arespreadable, semi-solid, gels. The term “gel” as used herein refers to aheterogeneous mixture containing a gelling agent, wherein at least onecomponent is dissolved in a liquid phase.

Ibuprofen useful in accordance with the invention includes thepharmaceutically acceptable salts and esters of ibuprofen, including theracemic mixture comprising the S- and R-enantiomers of ibuprofen, andthe substantially pure S-ibuprofen. “Substantially pure 5-ibuprofen”means at least 90% by weight S-ibuprofen and 10% or less by weight ofthe R-enantiomer of ibuprofen, at least 95% by weight S-ibuprofen and 5%or less by weight of the R-enantiomer of ibuprofen, or at least 98% byweight S-ibuprofen and 2% or less by weight of the R-enantiomer ofibuprofen.

Compositions of the invention include ibuprofen in an amount betweenabout 1% and about 30% by weight of the composition. In otherembodiments, the compositions comprise ibuprofen in an amount betweenabout 5% to about 20%, between about 5% to about 15%, and between about8% to about 11% by weight of the composition.

Ibuprofen has poor water solubility due to its relatively lipophilicnature. In view of this, it is important to take into consideration thatthe blend of ingredients in an ibuprofen composition be capable ofdissolving at least 5% by weight ibuprofen at room temperature. In oneembodiment, the solubility of ibuprofen in the blend of ingredients of acomposition at room temperature is greater than 10% by weight ofibuprofen of the composition. In certain embodiments, the solubility ofibuprofen in the blend of ingredients of a composition at roomtemperature is greater than 20% by weight. The blend of ingredients of acomposition may include a vehicle and optionally one or more otherexcipients. In certain embodiments, the vehicle comprises a non-volatilesolvent and a lower alkyl alcohol. In certain additional embodiments,the vehicle comprises one or more lower alkyl alcohol(s).

The lower alkyl alcohols may be, for example, ethanol, n-propanol,isopropyl alcohol, and mixtures thereof. The compositions may include alower alkyl alcohol, such as isopropyl alcohol. Further, thecompositions may comprise ethanol. In one embodiment, a compositionincludes more than one lower alkyl alcohol, such as a mixture of ethanoland isopropyl alcohol, for example. A lower alkyl alcohol can be addedquantum sufficient, such that the amounts may vary. Typically, a loweralkyl alcohol may be present in a composition in an amount of betweenabout 25% and about 70% by weight of the composition. In certainembodiments, a lower alkyl alcohol may be present in a composition in anamount of between about 35% and about 40%, between about 40% and about60%, or between 60% and 70% by weight of the composition.

In certain embodiments, compositions may include a non-volatile solvent,such as dimethyl sulfoxide (DMSO), N-methyl pyrrolidone, dimethylisosorbide, propylene glycol, hexlene glycol and benzyl alcohol. Thenon-volatile solvent may be present in a composition in an amount ofbetween about 20% and about 60% by weight of the composition, forexample. In certain embodiments, a non-volatile solvent may be presentin a composition in an amount of between about 30% and about 55%,between about 40% and about 50%, or between 42% and 48% by weight of thecomposition. In additional embodiments, a composition includes DMSO orN-methyl pyrrolidone in an amount between about 30% and about 55%,between about 40% and about 50%, or between about 42% and about 48% byweight of the composition.

An antioxidant or a chelating agent known in the art may be included ina composition, in particular, when DMSO is present in the composition.

In certain embodiments, a composition may include a non-volatile solventand one or more lower alkyl alcohol, such as a mixture of DMSO andisopropyl alcohol. In another embodiment, a composition may include amixture of DMSO, isopropyl alcohol and ethanol.

Compositions may exclude water, such as an anhydrous gel. In otherembodiments, the compositions may include water. Typically, whenpresent, the weight percent of water is less than the weight percent ofa lower alkyl alcohol in a composition. The compositions may includewater in an amount between about 0.1% and about 30% by weight of thecomposition. In certain embodiments, a composition may include water inan amount between about 0.1% and about 1%, between about 1% and about5%, between about 5% and about 15%, between about 8% and about 12%,between about 15% and about 30%, or between about 15% and about 25% byweight of the composition.

When water is present in a composition, the composition can have anapparent pH* in the range of 3.0-7.0, more specifically 4.0-5.0.

The compositions may include a gelling agent. Non-limiting examples ofsuitable gelling agents include carboxyvinyl polymers, methyl cellulose,ethyl cellulose, hydroxycellulose, hydroxyethyl cellulose (HEC),hydroxypropyl cellulose (HPC). An exemplary gelling agent ishydroxypropyl cellulose (KLUCEL® hydroxypropylcellulose manufactured byHercules, Wilmington, Del.). The gelling agent may comprise apolyacrylic acid polymer (PAA), such as Carbopol polymers which arepolymers of acrylic acid cross-linked with polyalkenyl ethers or divinylglycol. One non-limiting example of a crosslinked polyacrylate polymeris Carbopol® 980 polymer manufactured by Noveon, Inc.

A gelling agent may be present in a composition in an amount, forexample, between about 0.1% and about 10% by weight of the composition.In certain embodiments, a composition may include a gelling agent in theamount of between about 1% and about 5%, between about 1.5% and about 3%or between about 3.5% and about 4.5% by weight of the composition.

Compositions of the invention may include a glycol, particularly, alower alkyl glycol. Non-limiting examples of lower alkyl glycols (i.e.,C₂ to C₄ alkyl glycol) include ethylene glycol, propylene glycol(1,2-propanediol), 1,3-butylene glycol, glycerol, or mixtures thereof.One non-limiting example of a lower alkyl glycol is propylene glycol.The lower alkyl glycol may possess humectant properties and may impart amoisturizing effect to the skin after application. A lower alkyl glycolmay in addition or alternatively serve as a vehicle or solvent in thecomposition. A lower alkyl glycol may be present in an amount of betweenabout 1% and about 40% by weight of the composition. In certainembodiments, a lower alkyl glycol may be present in an amount of betweenabout 5% and about 25%, between about 5% and about 15%, or between about15% and about 25% by weight of the composition.

A composition may include a skin penetration enhancer (penetrationenhancer). A skin penetration enhancer refers to an agent that improvesthe rate of transport of ibuprofen through the skin surface. A skinpenetration enhancer may be present in any amount, such as an amount ofbetween about 0.1% and about 50% by weight of the composition. Incertain embodiments, a skin penetration enhancer may be present in anamount of between about 0.1% and about 25%, between about 0.5% and about10%, or between about 1% and about 5% by weight of the composition.Non-limiting examples of skin penetration enhancers include, sulfoxidessuch as dimethylsulfoxide (DMSO), ethers such as diethylene glycolmonoethyl ether (e.g. Transcutol®P manufactured by Gattefossé, Cedex,France), and surfactants such as sodium laurate, sodium lauryl sulfate,Tween® 20, 40, 60, 80 (manufactured by, Croda Inc, Edison, N.J.,U.S.A.); alcohols such as ethanol, propanol, benzyl alcohol; fatty acidssuch as lauric acid, oleic acid, valeric acid and isostearic acid; fattyacid esters such as isopropyl myristate, isopropyl palmitate,methylpropionate, and ethyl oleate; polyols and esters thereof such aspropylene glycol, ethylene glycol, glycerol, butanediol, polyethyleneglycol, and polyethylene glycol monolaurate; amides and othernitrogenous compounds such as urea, dimethylacetamide (DMA),dimethylformamide (DMF), 2-pyrrolidone, 1-methyl-2-pyrrolidone,ethanolamine, diethanolamine and triethanolamine; terpenes; alkanones.“Percutaneous Penetration Enhancers, eds.” Smith et al. (CRC Press,1995) provides an overview of the field and further backgroundinformation on enhancers.

The compositions may further include a moisturizer. Non-limitingexamples of moisturizers/emollients include, but are not limited to,isopropyl myristate, myristyl lactate, lauryl lactate, glycerin,lanolin, isopropyl palmitate, hexyl laureate, isostearyl alcohol, octyldodecanol, hexyl decanol, oleyl alcohol, decyl oleate, medium chaintriglycerides, linoleic acid and mixtures thereof.

Compositions of the invention may further include an organic base. Anorganic base may be utilized as an ion-pairing agent in an anhydrouscomposition. Without being bound by theory, it is hypothesized thatinclusion of an organic base results in the formation of complex betweenthe base and the carboxylic acid group of the ibuprofen and limits theionization potential of the ibuprofen. An organic base may be a primaryamine, a secondary amine, or a tertiary amine. Non-limiting examples oforganic bases include triethanolamine, diethanolamine,diisopropanolamine, and tromethamine lauramine oxide. In one embodiment,the organic base is triethanolamine.

The amount of base present in a composition may vary. Typically, a basemay be present in an amount of between about 0.1% and about 10%, orbetween about 3% and 8% by weight of the composition.

DMSO containing compositions of the invention may have a viscosity ofbetween about 40,000 cps and about 400,000 cps, or between about 100,000cps and about 300,000 cps, or between about 150,000 cps and about250,000 cps. Alcohol based compositions of the invention may have aviscosity of between about 5,000 cps and about 100,000 cps, betweenabout 10,000 cps and about 50,000 cps, or between about 15,000 cps andabout 35,000 cps. Low viscosity of the alcohol based compositions (e.g.,below about 100,000 cps) may facilitate the spreadability of thecompositions. Low viscosity may also result in more rapid diffusion ofthe ibuprofen within the composition and faster release from theformulation.

The invention also provides methods of producing the ibuprofencompositions described herein. In certain embodiments, a method includesmixing ibuprofen, DMSO, and a gelling agent to yield a gel. A method mayfurther include adding a lower alkyl alcohol and/or a skin penetrationenhancer to the gel.

In certain embodiments, a method comprises mixing ibuprofen, a loweralkyl alcohol, a lower alkyl glycol to yield a gel. A method also caninclude adding a skin penetration enhancer to the gel. In oneembodiment, a method includes adding water to the gel, and the pH of thegel is between about pH 4.0 and about pH 5.0.

In certain embodiments, a method comprises mixing ibuprofen, a loweralcohol, a non-volatile solvent and adding the gelling agent asdispersion in hot water, for example, at between 50° C. to 70° C., atbetween 55° C. to 65° C., or at about 60° C.

In another aspect, the invention provides methods for reducing pain orinflammation comprising administering to a dermal surface of a subjectin need of a reduction in pain or inflammation a topical composition ofthe present invention. The dermal surface may be, for example, the neck,the back, an arm, a hand, a foot, a leg, or a joint. The dermal surfacemay also be associated with various conditions, for example,lacerations, cuts, bruises, or insect stings. The composition may beapplied as needed onto a dermal surface of the subject in an amountsufficient for the ibuprofen to achieve a therapeutically effectiveconcentration to ameliorate the pain or inflammation. The compositioncan be used for the treatment of pain, inflammation, arthritis, musclespasm and associated symptoms in humans and animals.

EXAMPLES

The following examples are merely illustrative of the present inventionand they should not be considered as limiting the scope of the inventionin any way, as these examples and other equivalents thereof will becomeapparent to those skilled in the art in light of the present disclosureand the accompanying claims. All percentages used in the application arepercent weight by weight (w/w) unless otherwise noted.

All ingredients were obtained from commercial vendors. For example,S-(+)-ibuprofen was obtained from Shasun; (R/S)-ibuprofen and propyleneglycol NF were obtained from Fisher scientific (Spectrum); isopropylalcohol NF was obtained from Fisher Scientific (Mallinckrodt); isopropylmyristate NF and triethanolamine NF were obtained from FisherScientific; hydroxypropyl cellulose NF (Grade HXF) was obtained from DowPharmaceuticals (Ashland); hydroxypropyl cellulose NF (Grade H) wasobtained from Nisso (Nippon Soda Co. Ltd.).

Example 1 Preparation of Formulations 1-17

Formulation 1:

A formulation was prepared by mixing the following components.

Components % w/w (R/S)-Ibuprofen 10 Propylene Glycol 20 IsopropylMyristate 5 Hydroxypropyl Cellulose 2 Isopropyl Alcohol 63

Formulation 2:

A formulation was prepared by mixing the following components.

Components % w/w (R/S)-Ibuprofen 10 Propylene Glycol 20 Transcutol P 25Isopropyl Myristate 5 Hydroxypropyl Cellulose 2 Water 10 IsopropylAlcohol 28

Formulation 3:

A formulation was prepared by mixing the following components.

Components % w/w (R/S)-Ibuprofen 10 Propylene Glycol 10 Transcutol P 10Isopropyl Myristate 5 Tween 20 2 Hydroxypropyl Cellulose 2 BenzylAlcohol 5 Water 10 Isopropyl Alcohol 46

Formulation 4:

A formulation was prepared by mixing the following components.

Components % w/w (R/S)-Ibuprofen 10 Propylene Glycol 20 IsopropylMyristate 5 Hydroxypropyl Cellulose 2 Triethanolamine 5 IsopropylAlcohol 58

Formulation 5:

A formulation was prepared by mixing the following components.

Components % w/w (R/S)-Ibuprofen 10.0 Oleic Acid 2.5 HydroxypropylCellulose 4.0 Dimethyl Sulfoxide 45.0 Isopropyl Alcohol 38.5

Formulation 6:

A formulation was prepared by mixing the following components.

Components % w/w (R/S)-Ibuprofen 10 Propylene Glycol 20 IsopropylMyristate 5 Hydroxypropyl Cellulose 2 Ethanol 63

Formulation 7:

A formulation was prepared by mixing the following components.

Components % w/w S-Ibuprofen 10 Propylene Glycol 20 Isopropyl Myristate5 Hydroxypropyl Cellulose 2 Isopropyl Alcohol 63

Formulation 8:

A formulation was prepared by mixing the following components.

Components % w/w S-Ibuprofen 10.0 Oleic Acid 2.5 Hydroxypropyl Cellulose4.0 Dimethyl Sulfoxide 45.0 Isopropyl Alcohol 38.5

Formulation 9:

A formulation was prepared by mixing the following components.

Components % w/w Ibuprofen 10 Propylene glycol 10 Isopropyl myristate 5Hydroxypropyl cellulose 2 Ethanol (190 Proof) 73

Formulation 10:

A formulation was prepared by mixing the following components.

Components % w/w Ibuprofen 10 Propylene glycol 10 Transcutol P 25Isopropyl myristate 5 Hydroxypropyl cellulose 2 Ethanol (190 Proof) 48

Formulation 11:

A formulation was prepared by mixing the following components.

Components % w/w Ibuprofen 10 Propylene glycol 10 Isopropyl myristate 5Oleic acid 2 Hydroxypropyl cellulose 2 Ethanol (190 Proof) 71

Formulation 12:

A formulation was prepared by mixing the following components.

Components % w/w Ibuprofen 10 Propylene glycol 10 Glycerin 3 Tween 20 2Hydroxypropyl cellulose 2 Water 10 Ethanol (190 Proof) 63

Formulation 13:

A formulation was prepared by mixing the following components.

Components % w/w Ibuprofen 10 Propylene glycol 10 Isopropyl alcohol 18Isopropyl myristate 5 Hydroxypropyl cellulose 2 Ethanol (190 Proof) 55

Formulation 14:

A formulation was prepared by mixing the following components.

Components % w/w Ibuprofen 10 Propylene glycol 10 Isopropyl alcohol 18Isopropyl myristate 5 Hydroxypropyl cellulose 2 Water 10 Ethanol (190Proof) 45

Formulation 15:

A formulation was prepared by mixing the following components.

Components % w/w Ibuprofen 10.0 Propylene glycol 10.0 Isopropylmyristate 5.0 Hydroxypropyl cellulose 1.2 Carbopol 980 1.2 Ethanol (190Proof) 72.6

Formulation 16:

A formulation was prepared by mixing the following components.

Components % w/w Ibuprofen 15 Propylene glycol 10 Glycerin 3 Tween 20 2Hydroxypropyl cellulose 2 Water 10 Ethanol (190 Proof) 58

Formulation 17:

A formulation was prepared by mixing the following components.

Components % w/w Ibuprofen 20 Propylene glycol 10 Transcutol P 25Isopropyl myristate 5 Hydroxypropyl cellulose 2 Ethanol (190 Proof) 38

Comparative Formulation:

Ibuleve Maximum Strength Gel containing 10% w/w ibuprofen and otheringredients including industrial methylated spirit, carbomers,diethylamine and purified water. Ibuleve is manufactured by DDD Limited,Watford, Herts, WD18 7JJ, UK.

Example 2 In Vitro Skin Permeation Study

Tracer amounts of radiolabeled (¹⁴C)-R/S-Ibuprofen or (¹⁴C)-S-Ibuprofen(American Radiolabeled Chemicals, St Louis, Mo.) at approximately 0.50μCi/dose was added to Formulations 1-8. A single clinically relevantdose (5 mg/cm²) was applied to dermatomed human skin obtained from onesingle donor following elective surgery.

Percutaneous absorption was evaluated by mounting the dermatomed tissuein Bronaugh flow-through diffusion cells (0.9 cm diameter or 0.64 cm²area) at 32° C. Six replicates were performed for each formulation.Fresh receptor fluid, PBS containing 0.1% w/v sodium azide and 1.5%(w/v) Oleth-20, pH 7.4, was continuously pumped under the skin at anominal flow rate of 1.0 mL/hour and collected in 6-hour intervals.Following 24-hours of exposure, the residual formulation remaining onthe skin surface was removed by repeated tape stripping (3 strips/cell).Subsequently, the epidermis was physically separated from the dermis bygentle peeling. Tape strips, epidermis and dermis samples were digestedusing Solune 350 (Perkin Elmer, Chicago, Ill.). The quantity ofradioactivity in the tape-strips, epidermis, dermis, and receptor fluidsamples was determined using Ultima Gold XR scintillant and a Tricarb2900TR liquid scintillation counter (Perkin Elmer, Chicago, Ill.). Massbalance was also performed.

The accompanying FIG. 1 is a graph comparing the cumulative quantities(% of applied dose) of ibuprofen diffused through human skin over a24-hour period of time. The results show formulations 1, 2 and 5-8 haveincreased transdermal absorption of ibuprofen as compared to thecomparative formulation. For example, formulations 5 and 7 providesuperior skin permeation of ibuprofen that increased skin permeation ofibuprofen by at least 100% after 24 hours. Formulations 6 and 8increased skin permeation of ibuprofen by approximately 70% after 24hours. Formulations 1 and 2 increased skin permeation of ibuprofen byapproximately between 20% to 50% after 24 hours. Formulations 3 and 4exhibit cumulative ibuprofen permeation amounts similar to that of thecomparative formulation.

Example 3 Gel Formulations Stability Study

The formulations 1-8 were analyzed for stability of the ibuprofencomponent at three different temperatures. Each sample of theformulations (16 g) was packaged in a glass scintillation vial andplaced at 5° C., 25° C. and 40° C. and a repeated “freeze and thaw”cycles (three cycles). The repeated “freeze and thaw” cycles consistedof storage for 3 or 4 days at −20° C., followed by storage for 3 or 4calendar days at controlled room temperature of 25° C. The samples wereanalyzed by reverse phase HPLC with UV detection (220 nm) after 30 days.The percent of the ibuprofen concentration at each time point wasdetermined for the sample formulations. The results are summarized inTable 1 and Table 2.

Appearance and Viscosity of Gel Formulations Study

The physical appearance of the formulations were determined by visualinspection. The viscosity was measured using a Brookfield viscometer foreach formulation at the storage conditions described above. Theviscosity parameters were specified as follows: (i) chamber 13R, spindle29, 13 g sample size with a two minute equilibration period prior tomeasurement, or (ii) chamber 6R, spindle 14, 2.5 g sample size with atwo minute equilibration period prior to measurement. The results aresummarized in Tables 1 and 2.

TABLE 1 Stability, Appearance and Viscosity of Gel Formulationscontaining 10% (R/S)-Ibuprofen at 30 days (R/S)- Formu- StorageViscosity Ibuprofen lation Condition Appearance (cps) (% LC ) 1 T = 0Smooth slightly hazy gel 28700 102.7 Freeze/Thaw Conforms 32500 106.6 5° C. Conforms 28550 102.8 25° C. Conforms 31500 101.4 40° C. Conforms30550 100.3 2 T = 0 Smooth slightly hazy gel 30850 101.4 Freeze/ThawConforms 30600 99.7  5° C. Conforms 32850 102.3 25° C. Conforms 33400100.1 40° C. Conforms 31500 100.4 3 T = 0 Smooth slightly hazy gel 27650101.8 Freeze/Thaw Conforms 28800 101.9  5° C. Conforms 28000 100.7 25°C. Conforms 27550 100.7 40° C. Conforms 26250 99.9 4 T = 0 Smoothslightly hazy gel 29800 102.2 Freeze/Thaw Conforms 33350 99.8  5° C.Conforms 31700 100.9 25° C. Conforms 32950 100.3 40° C. Conforms 3065098.4 5 T = 0 Smooth viscous slightly 182000 101.1 yellowish gelFreeze/Thaw Conforms 208000 100.2  5° C. Conforms 219000 100.3 25° C.Conforms 224000 99.9 40° C. Conforms 208000 101.3 6 T = 0 Smoothslightly hazy gel 25150 101.9 Freeze/Thaw Conforms 22700 101.5  5° C.Conforms 21850 99.8 25° C. Conforms 23450 101.4 40° C. Conforms 2415097.1

TABLE 2 Stability, Appearance and Viscosity of Gel Formulationscontaining 10% (S)-Ibuprofen at 30 days S- Formu- Storage ViscosityIbuprofen lation Condition Appearance (cps) (% LC ) 7 T = 0 Smoothslightly hazy gel 28700 101.2 Freeze/Thaw Conforms 32600 101.1  5° C.Conforms 30750 100.3 25° C. Conforms 31250 99.7 40° C. Conforms 3150099.9 8 T = 0 Smooth viscous slightly 174000 100.5 yellowish gelFreeze/Thaw Conforms 182000 100.7  5° C. Conforms 218000 101.2 25° C.Conforms 195000 100.2 40° C. Conforms 181000 100.4

From the results presented above, all formulations exhibited acceptablephysical and chemical stability characteristics after 30 days of storageat 5° C., 25° C. and 40° C., and after the repeated “freeze and thaw”cycles (three cycles).

The stability and physical characteristics (appearance and viscosity) offormulation 1 was further studied after 2 months according the methodsdescribed above. The viscosity parameters were: chamber 13R, spindle 29,speed 20 rpm, 13 g sample size with a two minute equilibration periodprior to measurement. The results are summarized in Table 3.

TABLE 3 Stability, Appearance and Viscosity of Gel Formulation 1containing 10% (R/S)- Ibuprofen at 1 and 2-months. (R/S)- ChemicalAnalysis Storage Time Viscosity Ibuprofen Impurity 1 Impurity 2Condition (Month) Appearance (cps) (% LC) (Area %) (Area %) N/A T = 0Smooth 28700 102.7 Not Detected Not Detected slightly hazy gelFreeze/Thaw N/A Conforms 32500 106.6 Not Detected Not Detected  5° C. 1Conforms 28550 102.8 Not Detected Not Detected 2 Conforms 32250 101.2Not Detected Not Detected 25° C. 1 Conforms 31500 101.4 Not Detected NotDetected 2 Conforms 30900 101.3 Not Detected Not Detected 40° C. 1Conforms 30550 100.3 0.70 0.12 (RRT = 1.07) (RRT = 1.09) 2 Conforms31800 96.5 0.70 0.12 (RRT = 1.07) (RRT = 1.09)

From the results presented above, formulation 1 exhibited acceptablephysical and chemical stability characteristics after 1 and 2-months ofstorage at 5° C., 25° C. and 40° C., and after the repeated “freeze andthaw” cycles (three cycles).

Example 4 Solubility of Ibuprofen in Solvents and Solvent Blends

Excess ibuprofen was equilibrated overnight (>16 hr) at room temperaturein various solvents and solvent blends. The solubility of ibuprofen wasassessed visually. The solubility of ibuprofen results are shown inTables 4 and 5.

TABLE 4 S-Ibuprofen Solubility at Room Temperature Solvents S-IbuprofenSolubility (% w/w) Propylene glycol >23 Benzyl alcohol >23 Ethanol >23Hexylene glycol >23 PEG 400 >23 Isopropyl alcohol >23 Transcutol P >23Dimethyl isosorbide >20 Diethyl sebacate >23 Isopropyl myristate >16Myristyl lactate 4.7-9.1 Isostearyl alcohol <4.8 Isostearic acid <4.8Octyldodecanol <4.8

TABLE 5 (R/S) Ibuprofen and S-Ibuprofen Solubility in Solvent Blends atRT Solvent Blend No. 1 2 3 4 5 6 Solvents (% w/w) Propylene glycol 10 1010 10 10 10 Glycerin 3 — — — — — Tween 20 2 — — — — — Transcutol P — 25— — — — Isopropyl myristate — 5 25 15 5 5 Water 10 — — — 10 — Isopropylalcohol — — — 18 18 — Ethanol 63 38 43 35 35 73 Solubility Solubility of(R/S) >20 >20 >20 >20 >20 >20 Ibuprofen (% w/w) Solubility ofS-Ibuprofen >20 >20 >20 >20 >20 >20 (% w/w)

The results in Table 4 indicate that the solubility of both (R/S)Ibuprofen and S-Ibuprofen are greater than 20% w/w at room temperaturein all solvent blends tested.

Example 5 Preparation of Formulations 18-24

Formulation 18:

Components % w/w Amount (R/S)-Ibuprofen 5 12.5 g Propylene Glycol 2048.3 mL Isopropyl Myristate 5 14.7 mL Hydroxypropyl Cellulose 2 5.0 gIsopropyl Alcohol 68 217.7 mL

Formulation 19:

Components % w/w Amount (R/S)-Ibuprofen 5 12.5 g Propylene Glycol 2048.3 mL Isopropyl Myristate 5 14.7 mL Hydroxypropyl Cellulose 2 5.0 gIsopropyl Alcohol 68 217.7 mL Water 20 50.0 mL

Formulation 20:

Components % w/w Amount (R/S)-Ibuprofen 5 12.5 g Propylene Glycol 2048.3 mL Isopropyl Myristate 5 14.7 mL Hydroxypropyl Cellulose 0.5 1.25 gIsopropyl Alcohol 49.5 158.5 mL Water 20 50.0 mL

Formulation 21:

Components % w/w Amount (R/S)-Ibuprofen 5 12.5 g Propylene Glycol 2048.3 mL Isopropyl Myristate 5 14.7 mL Hydroxypropyl Cellulose 1 2.50 gIsopropyl Alcohol 49.0 156.9 mL Water 20 50.0 mL

Formulation 22:

Components % w/w Amount (R/S)-Ibuprofen 5 12.5 g Propylene Glycol 2048.3 mL Isopropyl Myristate 5 14.7 mL Hydroxypropyl Cellulose 2 5.0 gTriethanolamine 5 11.2 mL Isopropyl Alcohol 45.5 145.7 mL Water 17.543.8 mL

Formulation 23:

Components % w/w Amount (R/S)-Ibuprofen 10 25 g Propylene Glycol 20 48.3mL Isopropyl Myristate 5 14.7 mL Hydroxypropyl Cellulose 2 5.0 gIsopropyl Alcohol 45.5 145.7 mL Water 17.5 43.8 mL

Formulation 24:

Components % w/w Amount S-Ibuprofen 5 12.5 g Propylene Glycol 20 48.3 mLIsopropyl Myristate 5 14.7 mL Hydroxypropyl Cellulose 2 5.0 g IsopropylAlcohol 48 153.7 mL Water 20 50.0 mL

Formulations 18-24 were prepared according to one of the threemanufacturing processes I, II and III, as described below.

Manufacturing Process I: Ibuprofen was dissolved in isopropyl alcoholfollowed by addition of the remaining liquid ingredients. The solutionwas mixed by stirring using a magnetic stir bar. The solution wasmaintained at room temperature (e.g., ˜22° C.), and hydroxypropylcellulose was then added with stirring using an overhead paddle stirrer.

Manufacturing Process II: This process was carried out as described inProcess I except that the temperature of the mixture was maintained at60° C. throughout.

Manufacturing Process III: Ibuprofen was dissolved in the organicsolvents at 60° C. Hydroxypropyl cellulose was dispersed in water at 60°C. and stirred with a magnetic stirrer for about 10 min to produce afine dispersion free of large particles. The hydroxypropyl cellulosedispersion was then added slowly to the ibuprofen solution with stirringusing an overhead paddle stirrer. The resultant formulation was thenstirred for approximately 10-15 minutes at 1,000-1,500 rpm until thehydroxypropyl cellulose was completely dissolved.

Manufacturing Process II was used to prepare Batch 2 of Formulation 18and Batch 1 of Formulation 21.

Manufacturing process I was used to prepare Batch 1 of Formulation 18.The addition of hydroxypropyl cellulose to the ibuprofen solution atroom temperature (˜22° C.) resulted in incomplete dissolution ofhydroxypropyl cellulose. A significant amount of undissolved, partiallysolvated particles of hydroxypropyl cellulose was observed even afterstirring of the mixture for 30 min at 2,000 rpm. Complete dissolution ofhydroxypropyl cellulose into the formulation at room temperature wasachieved by storage for 1 hour in the refrigerator (˜5° C.), andsubsequently 5 hours at room temperature (˜22° C.) followed by manualshaking at room temperature for 30 min.

Manufacturing process II was used to prepare Batch 2 of Formulation 18.The rate and extent of the dissolution of hydroxypropyl cellulose wasimproved but remained incomplete by adding hydroxypropyl cellulose atelevated temperature (e.g., 60° C.). Complete dissolution ofhydroxypropyl cellulose into the formulation was achieved more readilyaccording to manufacturing process I by manual shaking as theformulation cooled to room temperature.

Several attempts to prepare Formulation 18 by first dispersinghydroxypropyl cellulose in isopropyl alcohol at 60° C. were made.However, due to the rapid gelling of the resulting mixtures, suchattempts were unsuccessful.

Manufacturing process II was also used to prepare Batch 1 of Formulation21.

Manufacturing process III was used to prepare formulations containing20% water, e.g., Formulations 19, 20, 22, 23, 24 and batch 2 ofFormulation 21.

Example 6 Visual Inspection

The results of the visual inspection of the Formulations prepared inExample 5 are provided in Table 6.

TABLE 6 Visual Appearance and Apparent pH* Values of the Batches ofIbuprofen Topical Gels, Initially and after 24 Hours at Room TemperatureFormulation 18 19 20 21 22 23 24 Batch 1 2 1 2 1 1 2 1 1 1 ManufacturingProcess I II III III III II III III III III API R,S-Ibuprofen USP (%)5.0 5.0 5.0 5.0 5.0 5.0 5.0 5.0 10.0 — S-Ibuprofen (%) — — — — — — — — —5.0 Excipients Propylene Glycol NF (%) 20.0 20.0 20.0 20.0 20.0 20.020.0 20.0 20.0 20.0 Isopropyl Myristate NF 5.0 5.0 5.0 5.0 5.0 5.0 5.05.0 5.0 5.0 (%) Triethanolamine NF (%) — — — — — — — 5.0 — ThickeningAgents Hydroxpropyl Cellulose 2.0 2.0 2.0 — 0.5 1.0 1.0 2.0 2.0 2.0(Klucel HXF) (%) Hydroxpropyl Cellulose — — — 2.0 — — — — — — (Nisso H))(%) Solvents Water (%) — — 20.0 20.0 20.0 20.0 20.0 17.5 17.5 20.0Isopropyl Alcohol NF 68.0 68.0 48.0 48.0 49.5 49.0 49.0 45.5 45.5 48.0(%) Apparent pH* 4.3-4.4^(x) 4.4-4.5^(x) 4.10 3.95 3.77 3.59 3.87 8.044.13 4.15 Observation Initially Clarity H H H Cl Cl SH Cl SH SH SHParticles ++ + − − + + − − − − Fish Eyes ++ + − − + + − − − − ThicknessSS SS SS HVL VL VVL VVL SS SS SS After 24 Hours Clarity H H Cl SH SH ClSH SH SH Particles − − − + +/− − − − − Fish Eyes +/− − − + +/− − − − −Thickness SS SS HVL VL HVL HVL SS SS SS ^(x)Due to the completelynon-aqueous nature of these formulations, the pH* value fluctuatedwithin a range. Clarity: Cl = clear, SH = slightly hazy, H = hazy, VH =very hazy; Cd = cloudy Thickness: VL = viscous liquid, HVL = highlyviscous liquid, SS = semi-solid

All formulations prepared by manufacturing process III were free ofvisible particles, and appeared to be either slightly hazy or hazy atthe completion of the formulation preparation and after 24 hours ofstanding at room temperature. Formulation 21 prepared by manufacturingprocess III (Batch 2) was free of visible particles and clear. However,Formulation 21 prepared by manufacturing process I (Batch 1) wasslightly hazy and contained a few translucent particles (“fish-eyes”).Yet, the fish-eyes in Formulation 21 Batch 1 disappeared after standingfor approximately 72 hours at room temperature.

Example 7

The effects of the concentrations of water, ibuprofen concentration (5%or 10%), ibuprofen stereochemistry (S- vs. R, S-forms), HPC (0.5%, 1.0%or 2.0%), IPA (45.5%-68.0%) and TEA concentration (0% or 5%) aredescribed below.

Effects of Concentrations of Hydroxypropyl Cellulose and Water

A partial 3×2 statistical design of experiments (DOE) was conducted todetermine the effects of hydroxypropyl cellulose concentration and waterconcentration on the visual appearance and the thickness of theformulations prepared in Example 5 (See FIG. 2). Two levels of waterconcentration (low, L=0%, high, H=20%) and three levels of hydroxypropylcellulose (HPC) (low, L=0.5%, mid, M=1.0%, high, H=2.0%) concentrationwere explored in the design.

The formulations were classified qualitatively as a “viscous liquid”(VL, free-flowing), a “highly viscous liquid” (HVL, slow-flowing) or a“semi-solid” (SS, nonflowing), according to the principles in thetopical drug decision tree published by the FDA in 2005, L. Buhse et al.Topical Drug Classification, Int. J. Pharm. 295, 101-112 (2005).

FIG. 2 shows all formulations containing 2% HPC (Klucel Grade HXF) witheither 0% or about 20% water were semi-solid at room temperature.Formulations containing 0.5% or 1% HPC with about 20% water were viscousor highly viscous liquids, respectively. Although the viscosities of theformulations were not measured quantitatively, the formulations free ofwater appeared stiffer in consistency and requiring more force to spreadthem over a flat surface than those containing 20% water. In addition tocontrolling the thickness of the formulation, the concentration of HPCalso affected the visual appearance, with the degree of haze increasingwith increasing concentration of HPC.

Replacement of HPC (Klucel Grade HXF, MW: 1.15 MDa) with a slightlylower molecular weight HPC (Nisso Grade H, MW: 910 mD), produced ahighly viscous liquid (cf. a semi-solid gel), demonstrating that boththe molecular weight and the concentration of HPC are importantvariables in determining the form of the gel (liquid vs. semi-solid).

Effects of Triethanolamine

The effects of triethanolamine was studied by comparing the visualappearance of Formulations 22 and 19. Formulation 22 contains 5%triethanolamine and is the closest in composition to Formulation 19which contains the same concentrations of R,S-ibuprofen (5%), isopropylmyristate (5%), hydroxypropyl cellulose (2%), and slightly lowerconcentrations of isopropyl alcohol (45.5% vs. 48.0%) and water (17.5%vs. 20.0%). Formulations 22 and 19 were visually indistinguishable whereboth were semi-solid gels that could be spread easily across a flatsurface. Formulation 22 contains 5% triethanolamine was somewhat lesshazy than the Formulation 19. These results indicated the inclusion of5% triethanolamine has very little effect on the visual appearance andthickness of the ibuprofen gels prepared.

Effects of Ibuprofen Concentration

Formulation 23 contains 10% (R,S)-ibuprofen and is the closest incomposition to Formulation 19, which contains 5% R,S-ibuprofen, the sameconcentrations of IPM (5%), HPC (2%), and slightly lower concentrationsof IPA (45.5% vs. 48.0%) and water (17.5% vs. 20.0%). Both Formulations23 and 19 were semi-solid gels that could be spread easily across a flatsurface. These results indicate the concentration of ibuprofen in therange 5-10% has very little effect on the visual appearance or thicknessof the ibuprofen gels prepared in this study.

Effects of Stereochemistry of Ibuprofen

Formulations 19 and 24 were identical in excipient composition anddiffered only in the stereochemistry of the drug substance. Formulations19 and 24 contain 5% (R,S)- and 5% (S)-ibuprofen, respectively. Theresults (Table 2) indicate the stereochemistry of ibuprofen (R,S vs. S)has very little effect on the visual appearance or the thickness of theibuprofen gels prepared in this study.

Effects of Apparent pH* Values

With the exception of Formulation 22, the apparent pH* 8 values of theformulations ranged between 3.59 (Formulation 21) and 4.50 (Formulation18), consistent with the presence of 5-10% ibuprofen, which is a weakacid. The higher apparent pH* value of Formulation 22 can be attributedto the presence of 5% triethanolamine, which is also a weak base.

Conclusions

For topical gels based on formulations containing fixed concentrationsof propylene glycol (20.0%), isopropyl myristate (5.0%), and varyingconcentrations of hydroxypropyl cellulose (0.5%, 1.0%, 2.0%), isopropylalcohol (45.5%-68.0%), water (0%-20.0%), triethanolamine (0, 5.0%) andeither R,S-ibuprofen (5.0% or 10.0%) or S-ibuprofen (5.0%), thefollowing conclusions can be drawn.

All formulations prepared with 2.0% hydroxypropyl cellulose (Klucel HXF)and either 5.0% or 10.0% ibuprofen (S-, or R,S-) were semi-solid gels atroom temperature.

Replacement of Klucel HXF with the same concentration (2.0%) of thehighest molecular weight grade (H) of hydroxypropyl cellulose from Nissoproduced a highly viscous liquid rather than a semi-solid gel.

Whereas all formulations containing 2% Klucel hydroxypropyl cellulose(Grade HXF) were semi-solid gels, those formulations containing 20.0%water could be spread more easily across a flat surface (suggesting alower viscosity of the gel).

There were no meaningful effects of the concentration of R,S-ibuprofen(5.0% vs. 10.0%), the stereochemical form of ibuprofen (5.0% S- vs. 5.0%R,S-) or the addition of 5.0% triethanolamine on the visual appearanceor the thickness of the gels. Additionally, the clarity of the gelsstored at room temperature for periods longer than 24 hours improvedover time and the differences in the clarity of the various formulationbecame less obvious.

Formulations containing 20% water can be prepared using a two-vesselmethod (according to manufacturing process III), in which the ibuprofenis dissolved in the liquid excipients in a first vessel, andhydroxypropyl cellulose is dispersed in water at 60° C. in a secondvessel. The content of the second vessel is then added to the content ofthe first vessel containing the ibuprofen solution.

Formations containing no added water can be prepared in a single vesselby first dissolving the ibuprofen in the solvents and then adding thehydroxypropyl cellulose directly to the ibuprofen solution. Heating themixture to 60° C. increased the rate and the extent of dissolution ofhydroxypropyl cellulose. However, complete dissolution of thehydroxypropyl cellulose in the ibuprofen gels containing no added waterprepared at room temperature required storage at room temperature for 48hours followed by shaking for 30 minutes. Complete dissolution ofhydroxypropyl cellulose in the ibuprofen gels containing no added waterprepared at 60° C. required shaking for 30 minutes required shaking asthe gel cooled to room temperature.

Example 8 Determination of “Pharmaceutical Elegance” of Formulations

Various physical appearances and characteristics such as clarity (Cl),color (C), particulates (P), thickness (T), odor (O), residue (R) andacceptability (A) are viewed as components of pharmaceutical elegance ofthe topical formulations, and they were evaluated for ten formulationsincluding formulations 9, 18, 19 and 21-24 prepared in the previousexamples and three commercial formulations: Neurofen Ibuprofen 5% Gel,DOC Ibuprofen 5% Gel and Boots Ibuprofen 5% Gel.

The physical appearances of the formulation samples were examined byhuman eyes one sample at a time, where each sample was placed in a clearvial against a white background based on the following rating scales:

Clarity (Cl): Clear=5; Slightly Hazy=4; Hazy=3; Very Hazy=2; Cloudy=1

Color (C) Colorless=5; Faint Yellow=4; Slightly Yellow=3; Yellow=2;Intense Yellow=1

Particulates (P) (vials were kept upright and rotated through 360degree): no visible particles=5; a few translucent “fish-eyes” (solvatedhydroxypropyl cellulose particles)=4; several very noticeable “fisheyes”=3; many “fish eyes” and a few white particles (undissolvedhydroxypropyl cellulose)=2; many large translucent lumps and whiteparticles=5

Thickness (T) (vials were turned slowly upside down and observed therate of gel falling from the bottom of the vial): semi solid (stays inplace or falls as a lump)=5; highly viscous liquid (flows veryslowly)=4; viscous liquid (flows slowly)=3; slightly viscous (flowsquickly)=2; free flowing liquid (flows immediately)=1

Odor (O): odorless=5; faint odor=4; very noticeable odor=3; strongodor=2; strong, unpleasant odor=1

Residue on drying (R): none=5; slightly sticky=4; sticky with slightresidue=3; sticky with significant residue=2; very sticky with stringyresidue=1

Pharmaceutical elegance scores including both unweighted (PE) andweighted (PE′) scores, were calculated from the following equations:

PE=(P+Cl+C+T+O+R)  (1)

PE′=PE×A  (2)

where A is a weighting factor assessed on the overall acceptability ofthe formulations (A=2 acceptable, A=1 marginally acceptable, A=0unacceptable). The rating of A is a subjective assessment based on priorexperience with gels.

The results of the visual inspection of the physical appearances andcharacteristics, and the calculated unweighted (PE) and weighted (PE′)pharmaceutical elegance are provided in Table 7.

TABLE 7 Assigned Values of Physical Appearances or Characteristics(Clarity, Color, Odor, Thickness, Odor, Residue and Acceptability) andCalculated Unweighted (PE) and Weighted (PE′) Pharmaceutical EleganceScores of the Formulations Formulations 21 8 19 Neurofen 23 24 Boots 22DOC 18 API R,S-Ibuprofen US 5.0 — 5.0 5.0 10.0 — 5.0 5.0 5.0 5.0S-Ibuprofen — 10.0 — — — 5.0 — — — — Excipients Propylene Glycol NF 20.0— 20.0 — 20.0 20.0 — 20.0 — 20.0 (%) Isopropyl myristate NF 5.0 — 5.0 —5.0 5.0 — 5.0 — 5.0 (%) Oleic Acid NF (%) — 2.5 — — — — — — — — DMSO,USP (%) — 45.0 — — — — — — — — Dimethylisosorbide (%) — — — — — — Unk¹ —— — Benzyl Alcohol (%) — — — 1.0 — — — — Unk¹ — Triethanolamine NF — — —— — — — 5.0 — (%) Thickening Agents Poloxamer (%) — — — Unk^(1,2) — —Unk¹ — — — Ethylhydroxy cellulose — — — Unk^(1,2) — — — — Unk¹ — (%)Hydroxpropyl cellulose 1.0 4.0 2.0 Unk^(,2) 2.0 2.0 — 2.0 2.0 NF (KucelHXF) (%) Diluents Water (%) 20.0 — 20.0 Unk¹ 17.5 20.0 Unk¹ 17.5 Unk¹ —Isopropyl Alcohol 49.0 38.5 48.0 — 45.5 48.0 Unk¹ 45.5 Unk¹ 68.0 NF (qs)(%) Pharmaceutical Elegance Formulations 21 8 19 23 24 22 18 Clarity(1-5) 3 3 4 5 3 4 5 4 5 3 Color (1-5) 5 4 5 5 4 5 5 5 5 5 Particulates(1-5) 4 4 4 5 3 4 5 4 3 4 Thickness (1-5) 1 5 4 3 4 4 5 4 2 5 Odor (1-5)2 2 4 4 3 3 2 3 4 3 Residue (1-5) 4 2 4 5 3 5 4 5 5 5 Acceptability (0,1, 2) 0 0 2 2 1 2 1 2 1 1 Unweighted Score 19 20 25 27 20 25 26 25 24 25(PE) Weighted Score (PE′) 0 0 50 54 20 50 26 50 24 25 ¹Concentration ofexcipients in commercial products not available ²Thickening agent inNeurofen unknown

Results and Discussion

The unweighted pharmaceutical elegance scores (PE) were calculated andranked for the formulations from highest (i.e., most desirable) tolowest (i.e., least desirable) as follows:

Neurofen 5% Ibuprofen Gel (PE=27) Boots 5% Ibuprofen Gel (PE=26)Formulation 18 (PE=25) Formulation 19 R (PE=25) Formulation 24 (PE=25)Formulation 22 (PE=25) DOC 5% Ibuprofen Gel (PE=24) Formulation 23(PE=20) Formulation 8 (PE=20) Formulation 21 (PE=19)

The unweighted pharmaceutical elegance scores are further summarized inFIG. 3.

It is noted that the presence of 5% ethanolamine (Formulation 22) or thereplacement of R, S-ibuprofen with the S-enantiomer did not change theunweighted PE score (25/30). The lower PE score of 20/30 for Formulation23 which contains 10% ibuprofen (other formulations contain 5%ibuprofen) was due to the combination of slightly lower score forclarity (3/5), particulates (3/5), odor (3/5) and residue (3/5). Thelower PE score (20/30) for Formulation 8 based on DMSO and oleic acidwas attributed mainly to the low scores for odor (2/5) and residue(2/5). The lowest PE score (19/30) for Formulation 21 was due to the lowscores for thickness (1/5) and odor (2/5).

All the formulations studied were designed to be semi-solid gels, exceptfor Formulation 21 which was a free-flowing liquid.

The weighted pharmaceutical elegance scores (PE′) were calculated andranked for the formulations (highest [most desirable] to lowest [leastdesirable]) as follows:

High (PE′=50-54) Neurofen 5% Ibuprofen Gel (A=2, PE′=54) Formulation 19(A=2, PE′=50) Formulation 24 (A=2, PE′=50) Formulation 22 (A=2, PE′=50)Medium (PE′=20-26) Boots 5% Ibuprofen Gel (A=1, PE′=26) Formulation 18(A=1, PE′=25) DOC 5% Ibuprofen Gel (A=1, PE′=24) Formulation 23 (A=1,PE′=20) Low (PE′=0) Formulation 21 (PE′=0) Formulation 8 (PE′=0)

The weighted pharmaceutical elegance scores are further summarized inFIG. 4.

The intermediate weighted pharmaceutical elegance scores assigned to thetwo commercial formulations (DOC and Boots, 5% ibuprofen Gels), andFormulations 18 and 23 can be attributed primarily to the followingfactors: DOC 5% Ibuprogen Gel: the presence of particulates and fastflowing nature; Boots 5% Ibuprogen Gel: a strong odor and slightlysticky nature; Formulations 18 and 23: hazy, thick gels with/without asticky residue.

The low weighted pharmaceutical elegance scores for Formulation 21 canbe attributed to the free-flowing liquid form. The low score forFormulation 8 can be attributed to the high thickness and potentiallymore difficult to spread, it was also sticky and easily leave asignificant residue behind after application.

Conclusions

Of the six prepared formulations of the study, three of the formulations19, 22 and 24 provided excellent Pharmaceutical Elegance and comparedvery favorably with the commercial formulation (Neurofen 5% IbuprofenTopical Gel) (Diagram 3). The components common to all three of theformulations disclosed are 5% ibuprofen (R,S- or S-), 5% hydroxypropylcellulose and 20% water. Inclusion of 5% triethanolamine did not appearto alter the pharmaceutical elegance and may provide some additionalbenefits from a skin permeability perspective.

Formulations 18 and 23 contain either no water or 10% R,S-ibuprofen,respectively, were considered acceptable and compared favorably with theother two commercial formulations DOC and Boots 5% Ibuprofen Gels.

The Pharmaceutical Elegance of Formulation 8 containing DMSO/oleic acidwas marginal.

Example 9 In Vitro Dermal Irritation EpiSkin Test

The potential for skin irritation of two different concentrations ofS-ibuprofen formulations and a placebo (vehicle control) were evaluatedin a in vitro dermal irritation EpiSkin (reconstructed human epidermis)test. The SkinEthic EpiSkin® test system has been validated by OECD testmethod (439) as an in vitro model to assess skin irritation potential.The test uses human keratinocytes derived from healthy donors, grown invitro to reconstruct a functional model of the human epidermis.

Formulations 25-27 were prepared according to the manufacturingprocesses II as described in Example 5 and the contents of theformulations are listed below.

Formulation 25:

Components % w/w S-Ibuprofen 10 Propylene Glycol 20 Isopropyl Myristate5 Hydroxypropyl Cellulose 2 Isopropyl Alcohol 43 Water 20

Formulation 26:

Components % w/w S-Ibuprofen 5 Propylene Glycol 20 Isopropyl Myristate 5Hydroxypropyl Cellulose 2 Isopropyl Alcohol 48 Water 20

Formulation 27 (placebo):

Components % w/w (R/S)-Ibuprofen 0 Propylene Glycol 21 IsopropylMyristate 5.3 Hydroxypropyl Cellulose 2 Isopropyl Alcohol 50.8 Water 21

Formulation 27 was used as a vehicle formulation as a negative control(potential vehicle effects).

Experimental Procedure

MTT Direct Reduction Test

The endpoint of the EpiSkin® assay for skin irritation is the estimationof cell viability by assaying the reduction ofmethylthiazoldiphenyl-tetrazolium bromide (MTT) to its formazanmetabolite by mitochondrial reductase. Some chemicals possess anintrinsic ability to perform this reduction. This can adversely affectthe assay results, since MTT may be converted to formazan in the absenceof metabolically viable cells. Therefore, before performing the EpiSkin®irritation assay, it was necessary to determine if the test items arecapable of reducing MTT to formazan.

Direct reduction of MTT by the test item was assessed by adding theformulations and control (10 to MTT solution in phosphate bufferedsaline (2 mL, 0.3 mg/mL MTT). The positive control was eugenol. Thenegative control was water. The formation of purple colored formazan wasvisually assessed after incubating for 3 h±5 min in a humidifiedincubator at 37° C. and a CO₂ level of 5%. Three replicate samples wereassessed for each formulation. None of the tested formulations reducedMTT to formazan.

EpiSkin® Irritation Assay

The assay was carried out according to the performance standardsspecified by OECD:

-   -   OECD (2010), In Vitro Skin Irritation: Reconstructed Human        Epidermis Test Method, OECD Guidelines for the Testing of        Chemicals No. 439, OECD, Paris.

Test System Set Up

EpiSkin® units were shipped on transport agar in sterile plates of 12individual units. Upon delivery, the condition of the EpiSkin® wasassessed by checking the pH and temperature indicators. EpiSkin® unitswere transferred to 12 well plates containing EpiSkin® maintenancemedium (2 mL). The tissues were then be incubated for 2 to 24 h in ahumidified incubator at 37° C. and a CO₂ level of 5% before proceedingwith exposure to the test formulations and control substances. Thenegative control was Dulbecco's phosphate buffered saline (PBS) and thepositive control was an aqueous solution of sodium dodecyl sulphate(SDS, 5%, w/v).

The formulations were applied to the skin “without dilution”. An aliquot(10 μL) of the undiluted formulations and control substances wereapplied to three replicate EpiSkin® tissues using a positivedisplacement pipette. The formulations and controls were gently spreadover the entire surface of the exposed skin using the applicator tip.

The EpiSkin® was exposed to the formulations and control substances for15 min±30 s. The EpiSkin® surface was then rinsed with PBS (ca 25 mL)and returned to a well containing fresh Maintenance Medium (2 mL). Thetreated EpiSkin® units were then incubated for 42 h±1 h in a humidifiedincubator at 37° C. and a CO₂ level of 5%.

MTT Assay

After the recovery period, EpiSkin® units were tapped dry andtransferred to wells containing a solution of MTT in EpiSkin AssayMedium (2 mL, 0.3 mg/mL). The tissues were then incubated for 3 h±5 minin a humidified incubator at 37° C. and a CO₂ level of 5%. At the end ofthe incubation, EpiSkin® units were patted dry on absorbent paper andthe central part of the membrane was collected with a biopsy punch. Theupper cellular layer of the biopsy was separated from the underlyingcollagen matrix using forceps and both pieces placed into labeledmicrocentrifuge tubes. Formazan was extracted from the EpiSkin® byincubating each biopsy in acidified isopropanol (500 μL) for 68 h in afridge at 4° C., protected from light. The cell viability of each tissuewas calculated from optical density absorption readings with referenceto the negative controls, which were assigned the nominal value of 100%viability.

Calculation of Cell Viability from MTT Assay Optical Density (OD)Readings

Optical Density (OD_(550 mm)) readings were transferred into MicrosoftExcel to allow further calculations to be performed.

Standard statistical techniques were used to calculate OD_(blank) mean:the average OD of the blank (acidified isopropanol containing) wells.The corrected OD for each sample or control was calculated bysubtracting the value of OD_(blank mean) from each reading:

OD_(corrected)=OD_(raw)−OD_(blank mean)

The % Viability for each sample and positive control was calculated asfollows:

% Viability=(OD_(corrected)/mean OD_(negative controls))×100

Standard statistical techniques were used to calculate the meanviability (with standard deviation) for each test formulation, placebo(vehicle), and positive control. Formulations are considered to beirritant to skin in accordance with GHS category 2 if the tissueviability after exposure and post-treatment incubation is less than orequal (S) to 50%.

Table 8 shows the results of % Viability for Formulations 25-27.

TABLE 8 Percentage Viability of EpiSkin Cultures Mean Mean RelativeRelative Relative Viability per Viability per Repli- Viability TissueTreatment SD Treatment cate ID (%) (%) (%) (%) PBS Solution Rep 1 104.40104.25 100.00 10.00 (Negative 104.10 Control) Rep 2 107.12 107.17 107.22Rep 3 88.58 88.58 88.58 Aqueous SDS Rep 1 19.05 19.00 23.36 11.71Solution 18.95 (5%, w/v) Rep 2 36.18 36.63 (Positive 37.08 Control) Rep3 13.81 14.46 15.12 Formulation Rep 1 89.79 90.49 88.95 5.41 25 (S-91.20 Ibuprofen Rep 2 93.32 93.42 10%, (w/w)) 93.52 Rep 3 82.33 82.9483.54 Formulation Rep 1 93.72 94.42 93.65 1.75 26 (S- 95.13 IbuprofenRep 2 90.70 91.65 5%, (w/w)) 92.61 Rep 3 93.52 94.88 96.24 FormulationRep 1 98.35 98.05 98.69 2.38 27 (Placebo) 97.75 Rep 2 96.64 96.69 96.74Rep 3 101.68 101.33 100.97

While the invention has been described and pointed out in detail withreference to operative embodiments thereof, it will be understood bythose skilled in the art that various changes, modifications,substitutions, and omissions can be made without departing from thespirit of the invention. It is intended therefore, that the inventionembrace those equivalents within the scope of the claims that follow.

1. A composition for transdermal administration of ibuprofen or saltsthereof comprising: ibuprofen in an amount between about 1% and about30% by weight of the composition; a gelling agent; and a non-volatilesolvent.
 2. The composition of claim 1, wherein the ibuprofen isS(+)-ibuprofen.
 3. The composition of claim 1, wherein the ibuprofen isin an amount between about 5% and about 15% by weight of thecomposition.
 4. The composition of claim 1, wherein the ibuprofen is inan amount between about 8% and about 11% by weight of the composition.5. The composition of claim 1, wherein the gelling agent is selectedfrom the group consisting of methyl cellulose, ethyl cellulose,hydroxycellulose, hydroxyethyl cellulose, hydroxypropyl cellulose,hydroxypropylmethyl cellulose, and mixtures thereof.
 6. The compositionof claim 1, wherein the gelling agent comprises hydroxypropyl cellulose.7. The composition of claim 1, wherein the gelling agent is in an amountbetween about 0.1% and about 10% by weight of the composition.
 8. Thecomposition of claim 1, wherein gelling agent is in an amount betweenabout 1% and about 5% by weight of the composition.
 9. The compositionof claim 1, wherein the non-volatile solvent is dimethyl sulfoxide(DMSO).
 10. The composition of claim 1, wherein the non-volatile solventis N-methyl pyrrolidone.
 11. The composition of claim 1, wherein thenon-volatile solvent is in an amount between about 30% and about 55% byweight of the composition.
 12. The composition of claim 1, wherein thecomposition further comprises a lower alkyl alcohol.
 13. The compositionof claim 12, wherein the lower alkyl alcohol is selected from the groupconsisting of ethanol, propanol, isopropyl alcohol, and mixturesthereof.
 14. The composition of claim 12, wherein the lower alkylalcohol is isopropyl alcohol.
 15. The composition of claim 12, whereinthe lower alkyl alcohol is in an amount between about 25% and about 70%by weight of the composition.
 16. The composition of claim 12, whereinthe lower alkyl alcohol is in an amount between about 35% and about 40%by weight of the composition.
 17. The composition of claim 1, whereinthe composition further comprises a skin penetration enhancer.
 18. Thecomposition of claim 17, wherein the skin penetration enhancer comprisesoleic acid.
 19. The composition of claim 17, wherein the skinpenetration enhancer is in an amount between about 0.1% and about 25% byweight of the composition.
 20. The composition of claim 17, wherein theskin penetration enhancer is in an amount between about 1% and about 5%by weight of the composition. 21-67. (canceled)